The Hunt for Biomarkers and Better Treatments in Advanced TNBC

Christina T. Loguidice
Published: Sunday, May 21, 2017
Adam M. Brufsky, MD, PhD

Adam M. Brufsky, MD, PhD

Approximately 1 million breast cancer cases are diagnosed annually worldwide, with about 17% (n = 170,000) being triple-negative breast cancer (TNBC).1 Most TNBCs, about 75%, have been considered “basal-like,” meaning their expression signature has been shown to be comparable to that of the basal/myoepithelial cells of the breast, with transcriptomic characteristics similar to tumors arising in BRCA1 germline mutation carriers;2 however, more recently, genomic analysis has shown TNBCs to have substantial transcriptional, mutational, and copy number heterogeneity, indicating these tumors are significantly more heterogeneous than previously thought.3,4 Such findings have helped spur new developments in treating patients with TNBC, a cancer field that has seen relatively few meaningful clinical advancements since the introduction of adjuvant taxane therapy approximately 20 years ago.4

In an OncLive Peer Exchange® discussion led by Adam M. Brufsky, MD, PhD, experts in breast malignancies reviewed some exciting new developments in TNBC. The discussion focused on BRCA testing and other predictive biomarkers and on the promise of 2 novel treatment approaches currently under investigation for TNBC: immunotherapy and anti-body–drug conjugates.

TNBC Heterogeneity and BRCA Testing

The complexity of TNBCs is increasingly being understood as gene expression profiling is revealing more subtypes. “We’re learning over the last couple of years that these really are likely a collection of multiple different diseases,” said Brufsky. The most recent classification, which revised a widely accepted earlier classification by the same investigators, breaks them into 4 tumor-specific subtypes: 2 basal-like (BL1 and BL2), a mesenchymal (M), and a luminal androgen receptor (LAR) subtype (Table 1).5 When using these subtypes to assess response to neoadjuvant chemotherapy, significant differences between patient groups have been observed, with a pathological complete response (pCR) found in 41% of BL1 patients, 29% of LAR patients, and 18% of BL2 patients.5 The relevance of these subtypes has yet to be elucidated in prospective studies, and these subtypes have the potential to guide patient selection with regard to some of the newer treatments that are being investigated in clinical trials, including immunotherapy and antibody–drug conjugates.4

Table 1. Commonly Accepted Molecular Subtypes of TNBC Based on Gene expression Profiling

BL indicates basal-like; LAR, luminal androgen receptor; M, mesenchymal. 

Currently, BRCA mutation status, which has been associated with an increased response to platinum agents and poly (ADP-ribose) polymerase (PARP) inhibitors, is the only biomarker that is being used in routine clinical practice to guide treatment. The NCCN Guidelines recommend BRCA mutation screening in any patient who develops TNBC at ≤60 years, regardless of family history or other risk factors.6 This is partially because BRCA status has been strongly correlated with TNBC, with 80% of BRCA1 mutation carriers and 50% of BRCA2 mutation carriers developing TNBC. However, the likelihood of BRCA mutations decreases with advancing age (present in 43.8% of those <40 years vs 16.6% of those >70 years).4,7 Although some panelists found this recommendation “pretty reasonable,” it doesn’t fully clarify the testing of patients over 60 years old with TNBC, which was a point of discussion during the Peer Exchange®.

View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: How Do We Leverage PARP Inhibition Strategies in the Contemporary Treatment of Breast Cancer?May 31, 20191.5
Community Practice Connections™: A Better Way to Stop Pain: Paths Toward Responsible Postsurgical Pain Management for Patients With Breast CancerMay 31, 20191.5
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